19-4847797-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_005817.5(PLIN3):c.728C>T(p.Ser243Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000297 in 1,613,620 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: PLIN3 NM_005817.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.27

Genes affected

PLIN3 (HGNC:16893): (perilipin 3) Mannose 6-phophate receptors (MPRs) deliver lysosomal hydrolase from the Golgi to endosomes and then return to the Golgi complex. The protein encoded by this gene interacts with the cytoplasmic domains of both cation-independent and cation-dependent MPRs, and is required for endosome-to-Golgi transport. This protein also binds directly to the GTPase RAB9 (RAB9A), a member of the RAS oncogene family. The interaction with RAB9 has been shown to increase the affinity of this protein for its cargo. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Aug 2009]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLIN3	NM_005817.5	c.728C>T	p.Ser243Leu	missense_variant	6/8	ENST00000221957.9
PLIN3	NM_001164189.2	c.728C>T	p.Ser243Leu	missense_variant	6/8
PLIN3	NM_001164194.2	c.692C>T	p.Ser231Leu	missense_variant	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLIN3	ENST00000221957.9	c.728C>T	p.Ser243Leu	missense_variant	6/8	1	NM_005817.5	P3
PLIN3	ENST00000585479.5	c.728C>T	p.Ser243Leu	missense_variant	6/8	1		A1
PLIN3	ENST00000592528.5	c.692C>T	p.Ser231Leu	missense_variant	6/8	2
PLIN3	ENST00000589163.5	c.407+20C>T		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152120 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000240 AC: 6 AN: 249808 Hom.: 0 AF XY: 0.0000222 AC XY: 3 AN XY: 135398

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000260 AC: 38 AN: 1461500 Hom.: 0 Cov.: 51 AF XY: 0.0000316 AC XY: 23 AN XY: 727052

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.0000198

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152120 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74290

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000322 Hom.: 0

Bravo AF: 0.0000529

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 14, 2023

The c.728C>T (p.S243L) alteration is located in exon 6 (coding exon 5) of the PLIN3 gene. This alteration results from a C to T substitution at nucleotide position 728, causing the serine (S) at amino acid position 243 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Uncertain	-0.070
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.23	T;.;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Benign	0.072	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.7	M;.;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-5.0	D;.;.
REVEL	Uncertain	0.45
Sift	Uncertain	0.0010	D;.;.
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		0.75	P;.;P
Vest4		0.86
MutPred		0.82		Loss of disorder (P = 0.0264);.;Loss of disorder (P = 0.0264);
MVP		0.34
MPC		0.26
ClinPred		0.89	D
GERP RS		4.4
Varity_R		0.69
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs750348493; hg19: chr19-4847809;